Non-opiate Treatment After Prenatal Opiate Exposure to Prevent Postnatal Injury to the Young Brain (No-POPPY)

Grants and Contracts Details

Description

The number of newborns that develop the constellation of drug withdrawal symptoms or Neonatal Abstinence Syndrome (NAS) in the US has increased to epidemic proportions.1, 2 This is consistent with the rise in prescribed and non-prescribed opiate use as well as with the rise in heroin use.3 Aside from increased hospital length-of-stay and costs, the pharmacologic treatment of NAS with morphine, which is the standard of care during the first few weeks of life, is highly concerning as it corresponds with a timeframe of rapid postnatal brain development.4 The reported effects of morphine on the developing brain include decreased neurogenesis, synaptogenesis, and corticogenesis,5-8 decreased brain size,9 and decreased brain volumes in older children with prenatal opiate exposure.10 Although methadone is also being evaluated for the treatment of NAS, its narcotic and opioid properties pose concerns. Additionally, response to treatment is highly variable and limited pharmacogenetic and metabolic activity data, which can be used to optimize therapy in this population, pose additional challenges in using any drug to treat NAS. Collectively, these issues present a critical need to evaluate and optimize the use of a non-opioid drug for treatment of NAS. The long term goals of our research are to establish the best pharmacological treatment for NAS and determine how pharmacologic treatment of NAS affects long-term developmental outcomes. The objective of this application, in pursuit of that goal, is to evaluate the effectiveness of clonidine, an รก2 adrenergic receptor agonist, as a treatment for neonates with NAS, in a randomized clinical trial. Our central hypothesis is that clonidine will effectively treat drug withdrawal manifestations in neonates. Preliminary clinical evidence supports this hypothesis. Clonidine has previously been reported by us 11 and others as a single drug therapy for NAS in small number of infants with relief of withdrawal symptoms12-15 and as an effective adjunctive treatment, when giving chloral hydrate or morphine.16-18 Mechanistically, prolonged opiate exposure results in activation of opiate receptors in the locus ceruleus, which contain clusters of noradrenergic cells.19, 20 With cessation of opiate supply, the inhibitory effect of chronic opiate on noradrenergic activity is lost, resulting in increased noradrenergic activity, which contributes to withdrawal symptoms.21 Clonidine has inhibitory effects on noradrenaline release in the locus ceruleus, decreasing noradrenergic neuronal activity and, consequently, decreasing withdrawal manifestations.22, 23 The rationale for the proposed research is that, once we understand how clonidine can be used optimally in the clinic to treat NAS, a safe medication will be available and it could potentially minimize complications associated increased length-of-stay in the hospital, healthcare costs and the deleterious opiate assaults on the developing brain that continue with postnatal opiate administration. This MPI project brings together the clinical expertise of Dr. Henrietta Bada and the pharmacology and modeling expertise of Drs. Markos Leggas and Chee Ng. This project was the result of a previous collaboration that tested this concept in a pilot study.11 To test our central hypothesis and accomplish the objective of this application we plan to pursue the following specific aims: 1. To determine whether the treatment of NAS with a non-opiate medication, clonidine, will be more effective than morphine. We hypothesize that clonidine-treated infants will have better neurobehavioral performance summary scores (self- regulation, motor/reflexes, stress/abstinence scales, etc.) using the NICU Network Neurobehavioral Scale (NNNS),24, 25 as compared to those treated with morphine. 2. To determine whether treatment of NAS with clonidine will result in better early childhood outcomes than those treated with morphine. We will test the hypothesis that compared to morphine treatment, clonidine treatment will result in higher language, cognitive, and motor functioning scores at adjusted ages of 6, 12, and 24 months as determined with Bayley Scales III,26 and lower behavior problem scores at 24 months adjusted age as determined by the Child Behavior Checklist.27 3. To build population pharmacokinetic/pharmacodynamic models and determine factors that affect exposure and response to morphine and clonidine. There is high variability in the response of infants with NAS following treatment with opioid drugs. We hypothesize that variability in response to a single drug therapy can be accounted for by pharmacogenetic factors and altered neonatal metabolic capacity. With respect to expected outcomes, this proposal will provide prospective evidence: 1) regarding the potential of clonidine treatment to result in a shorter time to control NAS, shorter total days of treatment, shorter hospital stay, and a less likely need for an adjunctive or second drug therapy; 2) regarding how opioid and non-opioid exposure affect early childhood development; 3) regarding factors that influence response to treatment. These results are expected to have an important positive impact, because they have the potential to provide fundamental information regarding the metabolic ontogeny of infants exposed to opioid drugs and, most importantly, to improve the long-term outcomes of children born to addicted mothers. Non-opiate treatment after prenatal opiate exposure to Prevent Postnatal Injury to the Young Brain (No-POPPY) REFERENCES 1. Patrick SW, Schumacher RE, Benneyworth BD, Krans EE, McAllister JM, Davis MM. Neonatal abstinence syndrome and associated health care expenditures: United States, 2000-2009. JAMA. 2012;307(18):1934-1940. 2. Shonkoff JP, Garner AS, Committee on Psychosocial Aspects of C, Family H, Committee on Early Childhood A, Dependent C, et al. The lifelong effects of early childhood adversity and toxic stress. Pediatrics. 2012;129(1):e232-246. 3. SAMHSA. Results from the 2012 National Survey on Drug Use and Health: National Findings: Center for Behavioral Health Statistics and Quality, National Survey on Drug Use and Health, 2011 and 2012.; 2012. 4. Dobbing J, Sands J. Head circumference, biparietal diameter and brain growth in fetal and postnatal life. Early Hum Dev. 1978;2(1):81-87. 5. Zagon IS, McLaughlin PJ. Opioid antagonist-induced modulation of cerebral and hippocampal development: histological and morphometric studies. Brain Res. 1986;393(2):233-246. 6. Zagon IS, McLaughlin PJ. Opioid antagonist (naltrexone) modulation of cerebellar development: histological and morphometric studies. J Neurosci. 1986;6(5):1424-1432. 7. Hammer RP, Jr., Ricalde AA, Seatriz JV. Effects of opiates on brain development. Neurotoxicology. 1989;10(3):475-483. 8. Hauser KF, McLaughlin PJ, Zagon IS. Endogenous opioid systems and the regulation of dendritic growth and spine formation. J Comp Neurol. 1989;281(1):13-22. 9. Naeye RL, Blanc W, Leblanc W, Khatamee MA. Fetal complications of maternal heroin addiction: abnormal growth, infections, and episodes of stress. J Pediatr. 1973;83(6):1055-1061. 10. Walhovd KB, Moe V, Slinning K, Due-Tonnessen P, Bjornerud A, Dale AM, et al. Volumetric cerebral characteristics of children exposed to opiates and other substances in utero. Neuroimage. 2007;36(4):1331-1344. 11. Bada HS, Sithisarn T, Gibson J, Garlitz K, Caldwell R, Capilouto G, et al. Morphine versus clonidine for neonatal abstinence syndrome. Pediatrics. 2015;135(2):e383-391. 12. Hoder EL, Leckman JF, Ehrenkranz R, Kleber H, Cohen DJ, Poulsen JA. Clonidine in neonatal narcotic-abstinence syndrome. N Engl J Med. 1981;305(21):1284. 13. Hoder EL, Leckman JF, Poulsen J, Caruso KA, Ehrenkranz RA, Kleber HD, et al. Clonidine treatment of neonatal narcotic abstinence syndrome. Psychiatry Res. 1984;13(3):243-251. 14. Leikin JB, Mackendrick WP, Maloney GE, Rhee JW, Farrell E, Wahl M, et al. Use of clonidine in the prevention and management of neonatal abstinence syndrome. Clinical toxicology. 2009;47(6):551-555. 15. O'Mara K, Gal P, Davanzo C. Treatment of neonatal withdrawal with clonidine after long-term, high-dose maternal use of tramadol. Ann Pharmacother. 2010;44(7-8):1342-1344. 16. Esmaeili A, Keinhorst AK, Schuster T, Beske F, Schlosser R, Bastanier C. Treatment of neonatal abstinence syndrome with clonidine and chloral hydrate. Acta Paediatr. 2010;99(2):209-214. 17. Agthe AG, Kim GR, Mathias KB, Hendrix CW, Chavez-Valdez R, Jansson L, et al. Clonidine as an adjunct therapy to opioids for neonatal abstinence syndrome: a randomized, controlled trial. Pediatrics. 2009;123(5):e849-856. 18. Surran B, Visintainer P, Chamberlain S, Kopcza K, Shah B, Singh R. Efficacy of clonidine versus phenobarbital in reducing neonatal morphine sulfate therapy days for neonatal abstinence syndrome. A prospective randomized clinical trial. J Perinatol. 2013;33(12):954-959. 19. Duman RS, Tallman JF, Nestler EJ. Acute and chronic opiate-regulation of adenylate cyclase in brain: specific effects in locus coeruleus. J Pharmacol Exp Ther. 1988;246(3):1033-1039. 20. Beitner DB, Duman RS, Nestler EJ. A novel action of morphine in the rat locus coeruleus: persistent decrease in adenylate cyclase. Mol Pharmacol. 1989;35(5):559-564. 21. Rasmussen K, Beitner-Johnson DB, Krystal JH, Aghajanian GK, Nestler EJ. Opiate withdrawal and the rat locus coeruleus: behavioral, electrophysiological, and biochemical correlates. J Neurosci. 1990;10(7):2308-2317. 22. Nestler EJ, Terwilliger R, Beitner D. Regulation by chronic clonidine of adenylate cyclase and cyclic AMP-dependent protein kinase in the rat locus coeruleus. Life Sci. 1989;45(12):1073-1080. 23. Aghajanian GK. Tolerance of locus coeruleus neurones to morphine and suppression of withdrawal response by clonidine. Nature. 1978;276(5684):186-188. Non-opiate treatment after prenatal opiate exposure to Prevent Postnatal Injury to the Young Brain (No-POPPY) 24. Lester BM, Tronick EZ, Brazelton TB. The Neonatal Intensive Care Unit Network Neurobehavioral Scale procedures. Pediatrics. 2004;113(3 Pt 2):641-667. 25. Lester BM, Tronick EZ, LaGasse L, Seifer R, Bauer CR, Shankaran S, et al. Summary statistics of neonatal intensive care unit network neurobehavioral scale scores from the maternal lifestyle study: a quasinormative sample. Pediatrics. 2004;113(3 Pt 2):668-675. 26. Bayley N. Bayley Scales of Infant and Toddler Development Edition III: Psychological Corporation; 2005. 27. Achenbach TM, Resorla LA. The Child Behavior Checklist (CBCL/1.5-5) Burlington, VT: Univeristy of Vermont, Research Center for Children, Youth, & Families.; 2000.
StatusActive
Effective start/end date5/1/17 โ†’ 2/28/23

Funding

  • National Institute on Drug Abuse: $3,548,936.00

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